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Publication numberUS6150541 A
Publication typeGrant
Application numberUS 09/367,387
Publication dateNov 21, 2000
Filing dateJun 10, 1998
Priority dateDec 14, 1995
Fee statusPaid
Publication number09367387, 367387, US 6150541 A, US 6150541A, US-A-6150541, US6150541 A, US6150541A
InventorsEric Didier, Michel Lavigne, Jean-Rene Authelin
Original AssigneeAventis Pharma S.A.
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Anticancer agent; antileukemia agent
US 6150541 A
Abstract
The present invention is directed to 4,10β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-19-norcyclopropa(g)tax-11-en-13α-yl (2r,3s)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate and a process for its preparation.
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Claims(6)
What is claimed is:
1. 4,10β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-19-norcyclopropa(g)tax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate.
2. A process for the preparation of 4,10β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-19-norcyclopropa(g)tax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate;
wherein 4,10β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-19-norcyclopropa(g)tax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate or its hydrate is crystallized from a mixture of water and an aliphatic alcohol containing 1 to 3 carbon atoms or from a mixture of water and a ketone containing 3 to 4 carbon atoms; and
further wherein the product obtained is dried under reduced pressure or is dried and optionally maintained under relative humidity conditions greater than or equal to 40%.
3. The process according to claim 2, wherein the water/alcohol or water/ketone final ratio by volume ranges from 3/1 to 1/3.
4. The process according to claim 2, wherein the alcohol is ethanol and the ketone is acetone.
5. The process according to claim 2, wherein the drying or the drying and optional maintaining under a relative humidity greater than or equal to 40% is carried out at a temperature of about 40 C. under a pressure of about 5 kPa and wherein said product contains between 3 and 5% of water.
6. The process according to claim 2, wherein the preparation is carried out directly from an ethanolic solution of 4,10β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-19-norcyclopropa(g)tax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate which is obtained by deprotection, in an acid medium, of the ester 4,10β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-19-norcyclopropa(g)tax-11-en-13α-yl (2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyloxazolidine-5-carboxylate.
Description

This application is a continuation-in-part of PCT/FR96/01957, filed Dec. 9, 1996, which claims priority based on French application No. 95-14841 filed Dec. 14, 1995.

The present invention relates to 4,10β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-19-norcyclopropa[g]tax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate and to its preparation.

4, 10β-Diacetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-19-norcyclopropa[g]tax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate exhibits notable anticancer and antileukaemic properties.

4,10β-Diacetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-19-norcyclopropa[g]tax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate is prepared according to the process which is described more particularly in International Application PCT WO 94/13654.

It has been found that 4,10β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-19-norcyclopropa[g]tax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate exhibits a stability which is markedly superior to that of the anhydrous product.

According to the invention, 4,10β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-19-norcyclopropa[g]tax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate can be obtained by crystallization of 4,10β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-19-norcyclopropa[g]tax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate or by recrystallization of the dihydrate from a mixture of water and an aliphatic alcohol containing 1 to 3 carbon atoms or from a mixture of water and a ketone containing 3 to 4 carbon atoms, followed by drying the isolated product under reduced pressure and by optionally maintaining in a relative humidity greater than or equal to 40% or by direct drying in an atmosphere with a relative humidity greater than or equal to 40%.

In order to carry out the process according to the invention, it may be particularly advantageous--to dissolve 4,10β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-19-norcyclopropa[g]tax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate or its hydrate in an aliphatic alcohol containing 1 to 3 carbon atoms or in a ketone containing 3 to 4 carbon atoms,

to treat the solution with water,

to seed the solution with the dihydrate and then to treat again with water,

to separate the crystals obtained, then

to dry them under reduced pressure and then optionally to maintain them in an atmosphere with a relative humidity greater than or equal to 40%, that is to say, by way of example for a relative humidity of 40%, drying under a residual pressure of approximately 1.33 kPa for a temperature of 25 C. and under a residual pressure of approximately 3.86 kPa for a temperature of 45 C.,

or to dry them directly in an atmosphere with a relative humidity greater than or equal to 40%, that is to say, by way of example for a relative humidity of 40%, drying under a residual pressure of approximately 1.33 kPa for a temperature of 25 C. and under a residual pressure of approximately 3.86 kPa for a temperature of 45 C.

Generally, 4,10β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-19-norcyclopropa[g]tax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate or its hydrate is dissolved in an excess of aliphatic alcohol, preferably ethanol, or in an excess of a ketone, preferably acetone. Preferably, the amount of alcohol or ketone is between 4 and 16 parts by volume with respect to the weight of 4,10β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-19-norcyclopropa[g]tax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate used.

Generally, the water is added such that the water/alcohol or water/ketone final volume ratio is between 1/3 and 3/1.

The 4,10β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-19-norcyclopropa[g]tax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate which crystallizes is separated, preferably by filtration or centrifuging. The drying or the optional maintaining in an atmosphere with a relative humidity greater than or equal to 40% is carried out under reduced pressure, generally of between 0.5 and 30 kPa, preferably in the region of 5 kPa, at a temperature of between 10 and 70 C., preferably in the region of 40 C.

The water activity isotherm of the product was studied. Thus, 4,10β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-19-norcyclopropa[g]tax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate samples, intentionally dehydrated by forced drying, were maintained in atmospheres of controlled relative humidity (HR) at 25 C. The water contents, determined by TGA, show that the products stabilize at contents in the region of 4% (between 3 and 5%) when the relative humidity is greater than or equal to 40% (theoretical water content of 4.15% for a dihydrate).

__________________________________________________________________________Water activity isotherm at 25 C.InitialInitial  drying form by   Residence  Form by  conditions XD Initial TGA RH % time Loss by TGA XD__________________________________________________________________________20 C.,Dihydrate     1.6%/32 to            0   18 days                     0.8%/34 to 170 C.                              Dihydrate  48 hours  71 C.  31 days 0.99%/33 to 55 C. Dihydrate                               1.3 kPa  Stability at 5 55 days                              1.69%/32 to 63 C. Dihydrate                                 weight from 71 11 55 days 1.17%/33                              to 65 C. Dihydrate    to 200 C. 20 19 days 1.96%/33 to 68 C. Dihydrate                                   31 days 2.06%/34 to 61 C.                              Dihydrate42 19 days 3.77%/33 to 65 C. Dihydrate 31 days 4.07%/34 to 60 C. Dihydrate58 19 days 3.30%/34 to 63 C. Dihydrate 31 days 3.59%/34 to 65 C. Dihydrate80 19 days 3.98%/34 to 63 C. Dihydrate 31 days 4.22%/34 to 65 C. Dihydrate98 19 days 4.61%/34 to 68 C. Dihydrate 31 days 4.63%/34 to 65 C. Dihydrate  60 C., Dihydrate 0.76%/32 to 0 35 days 0.85%/31 to 60                              C. Dihydrate  60 hours  170 C. 11 37 days 0.90%/31 to 60 C. Dihydrate  4.6 kPa   20 35 days 0.95%/32 to 54 C. Dihydrate42 35 days 3.51%/32 to 60 C. Dihydrate58 35 days 2.35%/32 to 60 C. Dihydrate80 35 days 3.75%/32 to 70 C. Dihydrate98 37 days 3.97%/32 to 60 C. Dihydrate__________________________________________________________________________

In order to use the process according to the invention, it is possible to work directly on the ethanolic solution of 4,10β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-19-norcyclopropa[g]tax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate obtained after deprotection in acid medium of 4,10β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-19-norcyclopropa[g]tax-11-en-13α-yl (2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyloxazolidine-5-carboxylate.

The following examples illustrate the present invention.

EXAMPLE 1

2 g of crude 4,10β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-19-norcyclopropa[g]tax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate and 20 cm3 of absolute ethanol were introduced into a three-necked flask. 20 cm3 of water were added over approximately 45 minutes to the stirred solution at 50 C. and the suspension obtained was then cooled to a temperature in the region of 20 C. After filtration, the product was washed on the filter with 20 cm3 of an absolute ethanol/water (1/1 by volume) mixture and the product was then dried at 40 C. under reduced pressure (5.3 kPa). 1.64 g of 4,10β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-19-norcyclopropa[g]tax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate, containing 3.8% by TGA (FIG. 5) of water (theoretical value of the water content of the dihydrate of 4.15%), are obtained. The yield obtained was approximately 80%. The XRPD (X-ray powder diagram) diagram represented by FIG. 1 showed that the product thus obtained exhibited the characteristics of the dihydrate.

The X-ray powder diagram was obtained using a Philips PW 1700 device with a cobalt anti-cathode tube (λK.sub.α1 =1.7889 Å), the sweeping was performed at an initial sweep angle of 5 2-Θ, final sweep angle of 40 2-Θ, with an increment of 0.02 2-Θ, at a rate of 1 second per increment and using a silicon pastille.

Thermogravimetric analysis (TGA) was carried out using a Perkin-Elmer TGA 7 thermobalance at the initial temperature of 25 C. and at the final temperature of 300 C. with a temperature gradient of 10 C. per minute.

EXAMPLE 2

515 g of crude 4,10β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-19-norcyclopropa[g]tax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate and 4 litres of absolute ethanol were introduced into a reactor purged with nitrogen. The suspension was heated at 35-40 C. until dissolution is complete and the reactor was placed under reduced pressure of 8 kPa. Approximately 8 litres of solvent were distilled off at constant volume, the reactor was continuously supplied with ethanol (8 litres). After returning the reactor to atmospheric pressure, the solution was clarified by passing through a filter equipped with a 0.45 μm filter cloth. After rinsing the filter with 1 litre of absolute ethanol, approximately 1.8 litres of water were added at 40 C. over 1 hour to the whole of the solution. After initiating with 8 g of 4,10β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-19-norcyclopropa[g]tax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate, the mixture was cooled at a temperature in the region of 20 C. for 15 hours. The suspension was then heated to 40 C. and then 1.66 litres of water were added over 4 hours. The mixture was cooled to a temperature in the region of 20 C. and left stirring for 17 hours. The suspension was filtered on sintered glass and the filtered product was washed with 1.25 litres of an alcohol/water (50/50 by volume) mixture. The product was dried in an oven at 35 C. at 5.3 kPa for 72 hours in the presence of a stock of water and then at 35 C. at 2.7 kPa for 8 hours without a stock of water and again at 35 C. at 5.3 kPa for 16 hours in the presence of a stock of water. 491 g of 4,10β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-19-norcyclopropa[g]tax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate containing 4.0% of water (earl Fischer) were thus obtained. The XRPD (X-ray powder diagram) diagram represented by FIG. 2 showed that the product thus obtained was in the form of a dihydrate (theoretical value of the water content of 4,10β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-19-norcyclopropa[g]tax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate of 4.15%).

The X-ray powder diagram was obtained under the conditions described in Example 1.

EXAMPLE 3

2 g of crude 4,10β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-19-norcyclopropa[g]tax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate and 20 cm3 of acetone were introduced into a three-necked round-bottomed flask. The solution obtained, which was stirred at a temperature in the region of 20 C., was treated with 20 cm3 of water over approximately 35 minutes. The suspension obtained was stirred for approximately 15 minutes. After filtration, the product was washed twice on the filter with 20 cm3 of an acetone/water (1/1 by volume) mixture and the product was then dried at 40 C. under reduced pressure (5.3 kPa). 1.28 g of 4,10β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-19-norcyclopropa[g]tax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate were thus obtained. The yield obtained was approximately 75%. The XRPD (X-ray powder diagram) diagram represented by FIG. 3 showed that the product thus obtained exhibited the characteristics of the dihydrate.

The X-ray powder diagram was obtained under the conditions described in Example 1.

EXAMPLE 4

120 g of 4,10β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-19-norcyclopropa[g]tax-11-en-13α-yl (2R,4S,5R)-3-tert-butoxycarbonyl-2-(4-methoxyphenyl)-4-phenyloxazolidine-5-carboxylate and 1.08 litres of ethyl acetate were introduced into a reactor purged with nitrogen. The suspension was stirred at a temperature in the region of 20 C. and then a solution of 3.25 cm3 of 36% hydrochloric acid in 17.6 cm3 of water was introduced. After maintaining for 3 hours 30 minutes, a solution of 3.5 g of sodium hydrogencarbonate in 350 cm3 of water was charged to the reactor and stirring was carried out for 15 minutes. After separation by settling and drawing off the aqueous phase, washing was carried out twice in succession with 350 cm3 of water. The organic phase was concentrated under reduced pressure at approximately 25 C. until a residual volume of 350 cm3 was reached and then 350 cm3 of absolute ethanol were introduced. Distillation under reduced pressure was resumed at approximately 30 C. until the ethyl acetate was exhaustively removed, while supplying with 1.5 litres of absolute ethanol. The solution was heated to 40 C. and then 470 cm3 of water were added over 15 minutes. The solution was seeded with a suspension of 1 g of 4,10β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-19-norcyclopropa[g]tax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate in a mixture of 40 cm3 of water and 40 cm3 of absolute ethanol. After maintaining for 15 hours at approximately 40 C., 410 cm3 of water were added over 4-5 hours and the suspension was then cooled to 20 C. After filtration and washing the product on the filter, the product was dried for 15 hours under reduced pressure (2.7 kPa) at 25 C. and then for 24 hours at 35 C. 102 g of 4,10β-diacetoxy-2α-benzoyloxy-5β,20-epoxy-1-hydroxy-9-oxo-19-norcyclopropa[g]tax-11-en-13α-yl (2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-3-phenylpropionate dihydrate, containing 4.3% of water (Karl Fischer), were thus obtained with a yield of approximately 93%. The XRPD (X-ray powder diagram) diagram represented by FIG. 4 showed that the product thus obtained exhibited the characteristics of the dihydrate.

The X-ray powder diagram was obtained under the conditions described in Example 1.

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US5723635 *Mar 18, 1994Mar 3, 1998Rhone-Poulenc Rorer S.A.Centrifugal partition chromatography
Non-Patent Citations
Reference
1 *ACTA Crystallograph. Sect. C: Crystal Structure Commun., vol. C46, No. 5, 190, pp. 781 784, 1990.
2ACTA Crystallograph. Sect. C: Crystal Structure Commun., vol. C46, No. 5, 190, pp. 781-784, 1990.
3 *Chemical Abstracts, vol. 113, No. 75, 1990.
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
CN100420681CApr 29, 2005Sep 24, 2008上海奥锐特国际贸易有限公司Production of polyenoic taxad alcohol trihydrate
Classifications
U.S. Classification549/510, 549/511
International ClassificationC07D305/14
Cooperative ClassificationC07D305/14
European ClassificationC07D305/14
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